PENINSULA HEALTH

c12 classification by the College of Intensive Care Medicine

• The Problem with Acute Renal Failure

• John Botha • MBChB M Med FCP(SA)FRACP FCICM Dip PG Echo Dip Neph • Director of Intensive Care Peninsula Health• Adjunct Clinical Professor Monash University

Peninsula Health, Winner – Metropolitan Health Service of the Year 2007 and 2009

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Why is Hospital Acquired AKI a problem for the bedside clinician?

• Renal Physiology is Complex• Markers of Renal Injury are not clinically used(or useful?)• Fluid management in Sepsis is Difficult and overzealous

administration is bad• The role of the endothelial glycocalyx in fluid distribution is important

and its integrity is difficult to measure• Fluid Types may impact on Renal Outcome• Therapies for AKI with RIFLE Risk and Injury are limited• High Intensity RRT has not proven benefit• Optimising Filter life is problematic• In patients who have RRT in ICU the outcomes is poor

Problematic physiology

1. The kidney is at risk of hyperoxia

2. The kidney is at risk of hypoxia

• The kidney has a high exposure to O2

• Oxygen tension is tightly regulated in all organs because high PO2 is toxic

• In the kidney superoxide production is tightly dependent on O2 availability

• The human kidney has structural antioxidant defences.

• Arteries and veins are closely associated• This facilitates counter-current diffusion and

enables a high degree of AV shunting

Renal veins have a unique peri-arterial structureIt facilitates diffusive O2 shunting

Close coupling of veins and arteries to achieve counter-current O2 diffusion

This shunting is dependent on Renal Blood Flow

The cortex and the medullaAre linked by shuntingIf the cortex is underperfusedMore AV shunting occurs in interlobular vessels This can lead to medullary ischemiaEven if medullary flow is preserved

Medullary PO2 is very low

The septic kidney: global renal blood flow

Intra-renal blood flowIn septic sheep

Intra-renal oxygenation

Cortico-medullary dissociation

Knowing global Or even intra-renal blood flow sayslittle about medullary oxygenation

Clinical implications

• Global renal blood flow may be dissociated from GFR, medullary flow and medullary O2

• Reliable ways to measure renal blood flow are not available

• If there were reliable therapies to increase renal blood flow the effect of this on GFR is unpredictable.

• The renal medulla is always at risk of hypoxia

Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challengesHilde R. H. de Geus, Michiel G. Betjes and Jan Bakker Clin Kidney J (2012) 5 (2): 102-108

Biomarkers for AKI• Functional markers- SCr and plasma/serum CyC• Up-regulated proteins -NGAL, KIM-1, L-FABP and IL-18• Low-molecular weight proteins -Urine CyC• Enzymes NAG,- a-GST, p-GST, GGT and AP

Markers of Renal Injury are not clinically used(or useful?)

The reported AUCs are disappointing ranging from 0.50 to 0.84, with oneor two exceptions, which can be explained by statistical ormethodological differences in study design.

The discriminatory function in heterogeneous populations is poor andinfluenced by pre-existing renal function and time of samplecollection with respect to the renal insult

Clinical appraisal of a patient using standard parameters such asSCr and diuresis remains the cornerstone for now

Reasonable to use biomarkers together with other parameters such as traditional clinical characteristics to optimize the accuracy of prediction of developing AKI

Acute Renal Failure in the Critically Ill Multinational Multicentre Study JAMA August 17 2005 Vol 294

SepticShock

Major Surg

CardioShock

HypoVol

Drug

HRS

ObstrUro

Other

47.5%

34.3% 26.9% 25.6%

19% 5.7%

2.6%

12.%

MORTALITY

0%

10%

20%

30%

40%

50%

60%

ICU WARD

Fluid management in Sepsis is Difficult and overzealous administration is bad

Fluid resuscitation in septic shock-A positive fluid balance and elevated central venous pressure are associated with increased mortality

• Boyd, John H. MD, FRCP(C); Forbes, Jason MD; Nakada, Taka-aki MD, PhD; Walley, Keith R. MD, FRCP(C); Russell, James A. MD, FRCP Critical Care medicine Feb 2011 Vol 32

Design

• VASST Study Patients: The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock

• A retrospective review of the use of intravenous fluids during the first 4 days of care.

• Based on net fluid balance, they determined whether fluid balance quartile correlated with 28-day mortality

Table 1

Table 1. Fluid intake, urine output, and net fluid balance at 12 hrs and cumulative day 4 balance

Copyright © 2011 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 31

Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality* Boyd, John H.; Forbes, Jason; Nakada, Taka-aki; Walley, Keith R.; Russell, James A.Critical Care Medicine. 39(2):259-265, February 2011.doi: 10.1097/CCM.0b013e3181feeb15

Figure 2

Figure 2.A, Cox survival curves, adjusted for age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and severity of shock (dose of norepinephrine),

are shown for fluid balance quartiles at 12 hrs.

Quartiles 3 and 4 have significant increases in mortality compared with both quartiles 1 and 2

. B, Cox survival curves, adjusted for age, APACHE II

score, and dose of norepinephrine, are shown for cumulative fluid balance quartiles at day 4. Quartiles 3 and 4 have significant increases in mortality compared with both quartiles 1 and 2.

Copyright © 2011 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 32

Table 2

Table 2. Hazard ratio for death according to fluid balance quartiles

Copyright © 2011 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 33

Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality* Boyd, John H.; Forbes, Jason; Nakada, Taka-aki; Walley, Keith R.; Russell, James A.Critical Care Medicine. 39(2):259-265, February 2011.doi: 10.1097/CCM.0b013e3181feeb15

• A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock

Next Question.

• Whether fluid balance was predictive of central venous pressure ?

• Whether a guideline-recommended central venous pressure of 8–12 mm Hg yielded a mortality advantage?

Figure 3

B, Day 4 fluid balance during the preceding 24 hrs does not correlate with central venous pressure nor with the dose of norepinephrine.

Copyright © 2011 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 36

Figure 3.A, Fluid balance on study enrolment (12 hrs) significantly correlates with central venous pressure and dose of norepinephrine, p < .001 in both cases.

Figure 4

. B, Cox survival curves, adjusted for age, APACHE II score, and dose of norepinephrine, are shown for CVP groups on day 4. There were no significant differences in mortality among groups.

Cright © 2011 Critical Care Medicine. Published by Lippincott Williams &

Wilkins.37

Figure 4.A, Cox survival curves, adjusted for age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and severity of shock (dose of norepinephrine), are shown for central venous pressure (CVP) groups at 12 hrs. Patients with a CVP of <8 mm Hg at 12 hrs have the lowest mortality followed by those with CVP of 8–12 mm Hg and patients with a CVP >12 mm Hg had the highest mortality

• Central venous pressure correlated with fluid balance at 12 hrs.

• On days 1–4, there was no significant correlation.

• At 12 hrs, patients with a central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8–12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg.

• There was no correlation between CVP and mortality at day 4

• However, in patients whose central venous pressure was <8 mm Hg

• Found a more positive fluid balance among survivors compared with non survivors

• Suggesting that there is a point at which too little fluid is indeed harmful

The Elusive Sweet Spot !!!!

©

Then of course how to administer the fluid?

A positive fluid balance is associated with a worse outcome in patients with acute renal failure.Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent JL; Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators. Crit Care. 2008;12(3):Jun 4.

An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial.RENAL Replacement Therapy Study Investigators,

Improved understanding of microvascular physiology allows explanation of the discrepancy between clinical findings during fluid therapy and the original Starling principle

The role of the endothelial glycocalyx in fluid distribution is important and its integrity is difficult to measure

MATERIAL AND METHODS: A total of 150 individuals were tested for levels of inflammatory markers (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], interleukin-6 [IL-6]) and glycocalix markers (syndecan-1, heparan sulfate). Three groups consisted of patients with severe sepsis or septic shock, patients after major abdominal surgery without systemic inflammatory response syndrome, and healthy volunteers. Blood was drawn, at the time of diagnosis or surgery, and 6, 24, and 48h later.

RESULTS: Levels of inflammatory markers were markedly higher in patients with sepsis compared with patients after major abdominal surgery and healthy volunteers. After major abdominal surgery, glycocalix markers in human plasma were at levels comparable to patients with sepsis. In patients with sepsis, levels of IL-6 correlated with syndecan-1, ICAM-1, VCAM-1, and lactate, while ICAM-1 furthermore correlated with CRP and lactate levels.

CONCLUSION: High levels of glycocalix markers indicated that significant flaking of the endothelial glycocalix occurred in patients with sepsis, and to a lesser extent in patients after major abdominal surgery. This novel finding could explain the nonspecific capillary leaking syndrome of patients with sepsis and after major abdominal surgery, and may identify new targets for treating those patient populations.

Natriuretic Peptide in the Critically Ill with Acute Kidney InjuryMassimo de Cal, Mikko Haapio, Dinna N. Cruz, Paolo Lentini, Andrew A. House, Ilona Bobek, Grazia M. Virzì, Valentina Corradi, Flavio Basso, Pasquale Piccinni, Angela D'Angelo, Jamie W. Chang, Mitchell H. Rosner, and Claudio Ronco Int J Nephrol. 2011; .

Increase in median of BNP of patients with AKI on admission

• In this pilot study, demonstrated for the first time an association between plasma BNP levels and AKI in critically ill patients.

• Patients with AKI have higher levels of BNP compared to no-AKI patients, and in AKI patients BNP levels continue to increase during the subsequent 48 hours.

• Results suggest that plasma BNP may distinguish the occurrence of AKI.

Fluid Type may impact Renal Outcome

Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care unitsSimon Finfer, Bette Liu, Colman Taylor, Rinaldo Bellomo, Laurent Billot, Deborah Cook, Bin Du, Colin McArthur, John Myburgh and SAFE TRIPS Investigators

Percentage of fluid resuscitation episodes given as crystalloid, colloid or blood product according to country

Type of colloid used as a percentage of all colloid episodes by country.

Chloride Restrictive

• Loop diuretics

• Mannitol

• Dopamine

Therapies for AKI with RIFLE Risk and Injury are limited

AIMThe primary aim of the study is to assess the effects of a continuous supplementary infusion of standard L-amino acids on renal function, renal failure and recovery from renal injury in critically ill patients who require at least three days of intensive care.

The effects of a continuous supplementary infusion of a standard mixture of L-amino acids will be compared to standard care with regards to the onset and severity of clinically significant renal dysfunction, need for RRT, renal recovery rates, need for ongoing dialysis, and health status (quality of life, physical function and overall survival) at follow-up 90 days after randomisation.

Nephro-protective effects of L-amino acids in critically ill patients:A multi-centre randomised controlled trial. Gordon S. Doig, Fiona Simpson, Elizabeth Sweetman, Philippa Heighes, Rinaldo Bellomo, Michael Reade, Peter Harrigan, Andrew Davies,Carol Pollock, John Botha, Douglas Chesher, and Prasad Devarajan

Therapeutic agents for the treatment of AKIAnti-inflammatory agentsb1 Integrin antagonist, adenosine receptor antagonist, mesenchymal stem cells, C5areceptor antagonist, IL-10, IL-6 antagonist,statins, erythropoietin, a melanocyte stimulatinghormone, haeme oxygenase-1 inducers(rapamycin), activated protein C, toll like receptor(TLR) blockers (Eritoran), sphingosine 2A agonist,fibrates, statins, peroxisome proliferatoractivared receptor (PPAR)-c agonist, minocycline,inducable nitric oxide (iNOS) inhibitor, insulin,ethyl pyruvate, C5-antagonists,alkaline phosphatase

Anti-apoptotic agents NGAL, adenosine receptor antagonist,mesenchymal stem cells, erythropoietin,a-melanocyte stimulating hormone, caspaseinhibitors, minocycline, guanosine, pifithrin-a,poly ADP ribose polymerase (PARP) inhibitor

Iron scavengers NGAL, apotransferrin, deferoxamine

Anti-oxidants Edavarone, stobadine, deferoxamine

Vasodilators Endothelin receptor antagonist, fenoldopam, anti natriuretic peptide

Growth factors Erytropoetin, hepatocyte growth factor

?

0%

10%

20%

30%

40%

50%

60%

Never Seldom Sometimes Often Always

Use of Frusemide

Lasix Bolus Lasix Infusion

What happens in practice?

Mean Arterial Blood Pressure targeted

0

20

40

60

80

100

120

60-70 70-80 >80

Nephrology consult

0

10

20

30

40

50

60

70

Never Seldom Sometime Often Always

Central Venous Pressure Monitoring

Monitor CVP

0%5%

10%15%20%25%30%35%40%45%50%

Never Seldom Sometimes Often Always

DOSE OF RRT: The VA/NIH STUDY

Intensity of Renal Support in Critically ill Patients

High Intensity RRT has no proven benefit

Randomisation

Intensive Management

Intermittent haemodialysis 6 times a week

If hemodynamically unstableCVVHDF 35 ml/kg/hr

Conventional Management

3 times a week

CVVHDF 20ml/kg/hr

END POINT Primary Endpoint 60 day all cause mortality

Primary Outcome

Death from any cause by day 60:

Intensive Strategy (53.5%)

Less Intensive Strategy (51.5%) (P Value 0.57)

Intensity of Continuous Renal-Replacement Therapy in Critically Ill PatientsThe RENAL Replacement Therapy Study Investigators

N Engl J Med 2009; 361:1627-1638

Trial Management, Grant ApplicantsRinaldo BellomoCelia BradfordDavid GattasDorrilyn Rajbhandari

StatisticianSerigne Lo – George Institute

7 TRIAL SITES

Auckland City (NZ)Shay McGuinness, Rachael ParkeAustin (VIC)Rinaldo Bellomo, Glenn EastwoodDandenong (VIC)Sanjiv Vij, Katherine Shepherd, Bridget O’BreeFrankston (VIC)John Botha, Sharon Allsop, David LewisMonash (VIC)Craig Walker, Pauline Galt, Tammy LamacRoyal North Shore (NSW)Celia Bradford, Anne O’ConnorRoyal Prince Alfred (NSW)David Gattas, Dorrilyn Rajbhandari, Heidi Buhr

SLHD (RPAH Zone) HREC Approval: X09-0068 & HREC/09/RPAH/98

The Heparin Citrate (THC) StudyOptimising Filter life is problematic

AIMTo test the hypothesis that

regional citrate anticoagulation

is more effective than regional heparin/protamine

anticoagulation

at maintaining functional filter lifein patients receiving CRRT

The Heparin Citrate Study ACTRN 12609001079235

INCLUSIONCommencing CRRT for acute renal failure

Suitable for intervention or control

Equipoise

Consent (prior or delayed)

At least 1 of: K>6.5, pH<7.2, urea>25, creatinine >300, oedema

Age <18y

Expected <24h in ICU

Contraindication to intervention or control (eg

liver, H.I.T)

Expected difficulty adhering to allocated group

EXCLUSION

The Heparin Citrate Study ACTRN 12609001079235

INTERVENTIONRegional citrate anticoagulation

Regional heparin/protamine

anticoagulation

CONTROL

The Heparin Citrate Study ACTRN 12609001079235

CRRT CIRCUIT ANTICOAGULATION

Between Sites: Different hardware, modalities, protocolsWithin Sites: Same hardware, modality. Same/v similar

starting blood flow and fluid flow rates

Unblinded (statistician was blinded)

PRIMARY OUTCOMEFunctional filter life

transmembrane pressure >300mmHgvisible clot obstructing flow / blood pumpother reason (free text)

Measured in time to clotting event (hours)

All free text reasons for stopping were adjudicated by 2 independent, blinded intenvisists, and any disagreements resolved by consensus

Deemed by consensus: clotted, didn’t clot, or unsure

The Heparin Citrate Study ACTRN 12609001079235

RESULTSBaseline Characteristics – diagnosis and severity

The Heparin Citrate Study ACTRN 12609001079235

Table. Baseline characteristics of the intervention and control groupCitrate (N=105) Heparin/protamine (N=107)

~ 12% cardiac surgery, ~8 %septic shock, well matched groups including severity of illness

APACHE III Diagnostic Group - no./total (%)Coronary artery bypass grafts 14/105 (13.3) 13/107 (12.1)

Renal disorders 10/105 (9.5) 7/107 (6.5)Sepsis with shock, non-urinary 8/105 (7.6) 7/107 (6.5)

Other respiratory diseases 6/105 (5.7) 7/107 (6.5)Valvular heart surgery 5/105 (4.8) 6/107 (5.6)

Other 62/105 (59.0) 67/107 (62.6)APACHE II score - mean(SD) 25.6 (7.6) 25.0 (6.9)Meeting criteria for severe sepsis - no./total (%) 45/105 (42.9) 32/107 (29.9)SOFA: patients scoring 3+ at time of randomisation, no./total (%)

Renal 45/101 (44.5) 51/106 (48.1)Cardiovascular 69/101 (68.3) 68/106 (64.2)

Respiratory 46/101 (45.5) 51/106 (48.1)Coagulation 5/101 (5.0) 3/106 (2.8)

Liver 3/101 (3.0) 7/106 (6.6)

RESULTSBaseline Characteristics – vent, inotrope, labs

The Heparin Citrate Study ACTRN 12609001079235

Table. Baseline characteristics of the intervention and control groupCitrate (N=105) Heparin/protamine (N=107)

~73% patients ventilated, ~67% inotropesWell matched at baseline for renal and haematological parameters

Mechanically ventilated - no./total (%) 77/105 (73.3) 75/107 (73.3)Receiving inotropes - no./total (%) 74/105 (68.4) 71/107 (66.4)Renal parameters - mean (SD)

Urea (mmol/L) 21.9 (13.3) 23.4 (13.8)Creatinine (µmol/L) 309 (157) 322 (177)

Phosphate (mmol/L) 2.02 (0.83) 1.94 (0.94)Urine output in 6h prior to randomisation (mL) 170 (262) 190 (222)

Haematological parameters - mean (SD)Haemoglobin (g/L) 98.0 (16.6) 98.3 (26.2)

Platelet count (x10^9/L) 209 (146) 215 (143)INR 1.5 (1.2) 1.4 (0.52)

APTT (s) 40 (18) 40 (14)

RESULTSPrimary Outcome

The Heparin Citrate Study ACTRN 12609001079235 • Includes the first filter in each patient ONLY

Citrate median 39h (100 filters*)vs

Hep/prot median 22.8h (104 filters*)

Log rank p= 0.0037

RESULTSNumber of Filters, Duration of CRRT

The Heparin Citrate Study ACTRN 12609001079235 * filter outcome adjudicated by 2 independent intensivists

Regional citrate anticoagulation was associated withuse of fewer filters, less clotted filters and

longer cumulative duration of CRRT

Number of filters included in the study*

CitrateHeparin/

protamineTotal

Clotted 226 310 536Didn't Clot 127 112 239

Unclear 37 45 82TOTAL 390 467 857

Duration of CRRT (hours) 8281 8015 16296

RESULTSPrimary Outcome

The Heparin Citrate Study ACTRN 12609001079235

Frailty Model Analysis: Hazard Ratios for FilterGroup Description Point Estimate 95% Wald Confidence Limits FilterGroup Hep/Prot vs Citr 2.029 1.359 3.028

Analysis of Maximum Likelihood Estimates

Parameter DF Parameter

Estimate Standard

Error Chi-Square Pr > ChiSq Hazard

Ratio Label FilterGroup Hep/Prot 1 0.70736 0.20429 11.9888 0.0005 2.029 FilterGroup 0

The hazard ratio for a filter experiencing clotting in the heparin/protamine group (compared to citrate) was

2.03 (95% CI 1.34-3.02, p<0.005)

Filters in the citrate group are half as likely to clot

Cox model with random effect by subject

CONCLUSION

During CRRT in ICU, regional citrate anticoagulation,compared to regional heparin/protamine anticoagulation is associated with

- Half the risk of filter clotting [HR for clotting in hep/prot group 2.03 (95% CI 1.34-3.02, p<0.005)]

- Median filter life 39h v 22.8h (p=0.0037)

- Fewer adverse events

The Heparin Citrate Study ACTRN 12609001079235

In patients who have RRT in ICU What about their outcome?

Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial Martin Gallagher Alan Cass, Rinaldo Bellomo, Simon Finfer, David Gattas, Joanne Lee, Serigne Lo, Shay McGuinness, John Myburgh, Rachael Parke, Dorrilyn Rajbhandari, for the POST-RENAL Study Investigators and the ANZICS Clinical Trials Group Membership of the POST-RENAL. February 11, 2014 PLOS medicine

Figure 2. Kaplan-Meier survival curve for all study participants from randomization to end of extended follow-up, shown by treatment group.

Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601. doi:10.1371/journal.pmed.1001601

> 76

< 56

Table 5. Cox multivariate model for long-term mortality from randomization.

Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601. doi:10.1371/journal.pmed.1001601

Table 4. Prevalence of CKD by eGFR and albumin to creatinine ratio in follow-up participants.

Gallagher M, Cass A, Bellomo R, Finfer S, et al. (2014) Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLoS Med 11(2): e1001601. doi:10.1371/journal.pmed.1001601http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001601

Found that patients with AKI treated with RRT in the ICU were at high risk of dying during the 3.5-year follow-up period; overall 31.9% of those surviving to 90 days died during the extended follow-up period.

The risk of dying was much greater than the risk of entering a maintenance dialysis program, with neither outcome being influenced by the use of a higher intensity of RRT.

The rate of albuminuria in survivors was substantial, despite relative preservation of renal function

• Consider causes other than ATN.• Be mindful of Nephrotoxic drugs.• Restore MAP and ignore CVP after a few days in ICU • Fluid overload is bad and fluid therapy in ICU is a dynamic

process.• After initial resuscitation aim for a neutral or negative fluid

balance• Synthetic colloids should be avoided• Consider Citrate • Follow up of survivors should be considered with attention to

strategies to decrease albuminuria

PENINSULA HEALTH

• Thank You

Peninsula Health, Winner – Metropolitan Health Service of the Year 2007 and 2009

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